(1) Field of the Invention
The present invention provides novel anthracycline glycoside derivatives belonging to rhodomycin-group, and relates to a process for the production thereof, and more particularly, the present invention relates to the novel derivatives of anthracycline glycoside of the general formula I: ##STR1## wherein R.sup.1 is a hydrogen atom or hydroxyl group, and
R.sup.2 is a hydrogen atom or the following sugar chain: PA1 .epsilon.-rhodomycin RDC, .epsilon.-isorhodomycin RDC, .beta.-rhodomycin RDC, .gamma.-rhodomycin RDC, .gamma.-rhodomycin RDRs and .beta.-pyrromycin RDC PA1 R is rhodosamine, D is 2-deoxyfucose, C is cinerulose and Rs is rhodinose residue, respectively, and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formula I have the following combinations of definition in said compounds PA1 -o-r-d-c is --O--rhodosamine-2-deoxyfucosecinerulose residue and PA1 -o-r-d-r is --O--rhodosamine-2-deoxyfucoserhodinose
--O--rhodosamine-2-deoxyfucose-cinerulose residue ##STR2## and R.sup.3 is a hydroxyl group or carbomethoxy(--COOCH.sub.3) group or the foregoing sugar chain, --O--rhodosamine-2-deoxyfucose-cinerulose residue, or the following sugar chain: --O--rhodosamine-2-deoxyfucose-rhodinose residue ##STR3## and R.sup.4 is a hydrogen atom or hydroxyl group, and to a process for the production thereof.
(2) Description of the Prior Art
A number of anthracycline glycosides have been found in the culture medium of Streptomyces, and described in prior literature. Among them, daunomycin and adriamycin have already been applied clinically for human cancers.
Rhodomycinones, iso-rhodomycinone and rhodomycin-related antibiotics are described in Chem. Ber. 88, 1792-1818 (1955); Chem. Ber. 101, 1341-1348 (1968); J. Med. Chem., 20, 957-960 (1977); Pharmacie 27, 782-789 (1972); Zeit. Allg. Mikrobiol., 14, 551-558 (1974); Tetrahed. Lett. No. 38, 3699-3702 (1973); Folia Microbiol., 24, 293-295 (1979); and J. Antibiotics, 32, 420 (1979).
Aclacinomycin A is disclosed in U.S. Pat. No. 3,988,315 and by Oki et al. in J. Antibiotics 28, 830 (1975) and 32, 791-812 (1979).
Cinerubins A and B are disclosed in U.K. Pat. No. 846,130, U.S. Pat. No. 3,864,480, Keller-Schierlein et al., "Antimicrobial Agents and Chemotherapy," page 68 (1970), Chemical Abstracts 54, 1466i (1960) and J. Antibiotics 28, 830 (1975).
Further illustrative and summary disclosures of anthracycline antibiotics can be located in Index of Antibiotics from Actinomycetes, Hamao Umezawa, Editor-in-chief, University Park Press, State College, Pennsylvania, U.S.A. (1967) as follows:
______________________________________ Antibiotics Page numbers ______________________________________ Aclacinomycins A and B 101-102 Adriamycin 122 Carminomycin I 225 Galirubins S - D 405-408 Rhodomycins X - Y 879-880 .beta.-Rhodomycins 881-885 .gamma.- Rhodomycins 886-892 Steffimycin 945 ______________________________________
The textbook, Antibiotics, Volume 1, Mechanisms of Action, edited by David Gottlieb and Paul D. Shaw, Springer-Verlag New York, Inc., N.Y. (1967) at pages 190-210 contains a review by A. DiMarco entitled "Daunomycin and Related Antibiotics."
Information Bulletin, No. 10, International Center of Information of Antibiotics, in collaboration with WHO, December, 1972, Belgium, reviews anthracyclines and their derivatives.
In their continuation of a study on biogenesis and biosynthesis of anthracycline antibiotics, especially aclacinomycins produced by Streptomyces galilaeus and rhodomycins produced by Actinomyces roseoviolaceus or Streptomyces purpurascens, the present inventors have developed an unique method for obtaining new anthracycline antibiotics from biologically inactive anthracyclinone by microbial glycosidation, and applied it to the search for useful anthracycline antibiotics having more potent antitumor activity and lower toicity than adriamycin and daunomycin, which are widely used as cancer chemotherapeutic agents. As a result, they found that aclacinomycin-producing microorganisms (Japan Patent Kokoku No. SHO 51-34915, Japan Patent Kokai No. SHO 53-44555, Japan Patent Kokai No. SHO 54-63067), for example, Streptomyces galilaeus MA 144-M1 (ATCC 31133, FERM-P 2455), and mutants therefrom, produced new rhodomycin-group antibiotics from various anthracyclinones such as .epsilon.-rhodomycinone, .gamma.-rhodomycinone, .beta.-rhodomycinone, .epsilon.-isorhodomycinone and .epsilon.-pyrromycinone by the microbial glycosidation, confirmed that these antibiotics, named as rhodomycins RDC or RDRs and pyrromycin RDC, are new compounds which have potent antitumor activity and low toxicity in animals, and established the processes and method for their preparation and purification.